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CHEMISTRY
K. Yu. Novitskii, Yu. K. Yur’ev, V. N. Zhingareva, E. F. Egorova
SYNTHESIS OF SYMMETRICAL 3,4-BIS(DIALKYLAMINOMETHYL)FURANS
(Presented by Academician A. N. Nesmeyanov on 27 VI 1962)
In previous communications ($^1,^2$) we described a method for the synthesis of symmetrical 2,5-bis(dialkylaminomethyl)furans, the diiodomethylates of which possess a clearly pronounced ganglion-blocking action ($^3$). To determine the dependence of the physiological activity of the diiodomethylates on the position of the aminomethyl group in the furan nucleus, we synthesized symmetrical 3,4-bis(dialkylaminomethyl)furans containing no substituents in the 2 and 5 positions of the ring. Diamines of this structure have not been described in the literature; only 2,5-diphenyl-3,4-bis(dialkylaminomethyl)furans are known, obtained by Lutz et al. ($^4$) by the action of secondary amines on 2,5-diphenyl-3,4-bis(chloromethyl)furan.
The method we developed for the synthesis of 3,4-bis(dialkylaminomethyl)furans is based on the use of 3,4-bis(oxymethyl)furan (I), which, under the action of thionyl chloride in the presence of pyridine, was converted into 3,4-bis(chloromethyl)furan (II). The reaction of dichloride (II) with secondary amines proceeded readily and led to 3,4-bis(dialkylaminomethyl)furans (III) (a, b, c, d, e) in yields of 55–91%.
\[
\mathrm{HOCH_2}\text{-furan-}\mathrm{CH_2OH}
\ \xrightarrow[\mathrm{C_5H_5N}]{\mathrm{SOCl_2}}\
\mathrm{ClCH_2}\text{-furan-}\mathrm{CH_2Cl}
\ \xrightarrow{\mathrm{R_2NH}}\
\mathrm{R_2NCH_2}\text{-furan-}\mathrm{CH_2NR_2}
\]
\[
\text{(I)} \qquad\qquad\qquad\quad \text{(II)} \qquad\qquad\qquad\quad \text{(III) (a, b, c, d, e)}
\]
\[ \mathrm{NR_2} = \text{a) } \mathrm{N(CH_3)_2}; \quad \text{b) } \mathrm{N(C_2H_5)_2}; \]
\[ \text{c) } N\text{-pyrrolidino}; \quad \text{d) } N\text{-piperidino}; \quad \text{e) } N\text{-morpholino}. \]
In this way 3,4-bis(dimethylaminomethyl)-, (diethylaminomethyl)-, (N-pyrrolidinomethyl)-, (N-piperidinomethyl)-, and (N-morpholinomethyl)furans were obtained. It should be noted that 3,4-bis(chloromethyl)furan (II), in contrast to 2,5-bis(chloromethyl)furan, can be stored for a long time in the absence of solvent even at room temperature. The 3,4-bis(dialkylaminomethyl)furans are also more stable than the corresponding 2,5-isomers.
We also studied the reduction of N,N-substituted diamides of furan-3,4-dicarboxylic acid, obtained by reaction of the dichloranhydride of this acid with amines, and in this way synthesized 3,4-bis(pyrrolidinomethyl)furan, identical with III c:
\[
\mathrm{ClOC}\text{-furan-}\mathrm{COCl}
\ \longrightarrow\
\mathrm{R_2NOC}\text{-furan-}\mathrm{CONR_2}
\ \longrightarrow\
\mathrm{R_2NCH_2}\text{-furan-}\mathrm{CH_2NR_2}
\]
\[
\text{(V)}
\]
Experimental Part
3,4-Bis(oxymethyl)furan (I). A solution of 18 g of diethyl furan-3,4-dicarboxylate ($^5,^6$) in 150 ml of absolute ether was added dropwise to 7.6 g of lithium aluminum hydride in 300 ml of ether; the mixture was boiled for one hour, left overnight, and decomposed with 200 ml of a 20% solution of Rochelle salt.
The ether layer was separated, and the aqueous layer was extracted for 30 h in an extractor with ether. After removal of the ether and distillation of the residue in vacuum, 9 g (83%) of the diol was obtained; it is a viscous colorless liquid, solidifying on cooling: b.p. 137–138° (3 mm); 129–130° (2 mm); $n_D^{20}$ 1.5080; $d_4^{20}$ 1.2390. $MR_D$ 30.62. $\mathrm{C_6H_8O_3F_2}$. Calculated $MR_D$ 31.46. Literature data: b.p. 146–148° (6 mm); $n_D^{25}$ 1.5021 (7); b.p. 120° (1 mm); $n_D^{20}$ 1.4970 (8); b.p. 115–120° (1 mm); $n_D^{27}$ 1.5073 (9).
3,4-Bis(chloromethyl)furan (II). To a solution of 12 g of (I) in 35 ml of abs. chloroform and 20 ml of pyridine, a solution of 21 ml of thionyl chloride in 15 ml of chloroform was added dropwise at $-5 \div -10^\circ$. The mixture was kept for 1 h at 20° and poured onto ice. The chloroform layer was separated, washed twice with diluted (1:10) hydrochloric acid, with 3% sodium hydroxide solution in the presence of ice, and dried over potash. After removal of the solvent and distillation in vacuum under nitrogen, 8.4 g (54%) of dichloride II was obtained: a colorless liquid, crystallizing on cooling to colorless plates; readily soluble in benzene and chloroform, poorly soluble in ether; m.p. 28–29°; b.p. 86–87° (6 mm).
Found, %: C 43.84, 44.06; H 4.01, 4.02; Cl 43.56
$\mathrm{C_6H_6OCl_2}$. Calculated, %: C 43.64; H 3.67; Cl 43.03
3,4-Bis(dimethylaminomethyl)furan (IIIa). To 15 g of dimethylamine in 75 ml of abs. ether and 2 g of powdered potassium hydroxide, 3.5 g of dichloride II in 20 ml of benzene was added. The mixture was boiled for 2 h, left overnight, and the precipitate was separated and washed with ether. After removal of the ether and distillation of the residue in vacuum under nitrogen, 3.2 g (82%) of IIIa was obtained: a colorless mobile liquid with a characteristic amine odor: b.p. 81–82° (6 mm); $n_D^{20}$ 1.4707; $d_4^{20}$ 0.9427; $MR_D$ 53.93, $\mathrm{C_{10}H_{18}ON_2F_2}$. Calculated $MR_D$ 54.77.
Found, %: C 65.76, 65.60; H 9.88, 10.04
$\mathrm{C_{10}H_{18}ON_2}$. Calculated, %: C 65.89; H 9.95
Dipicrate: m.p. 139–140° (from alcohol), light-yellow lustrous crystals.
Found, %: C 41.58, 41.68; H 4.20, 4.13
$\mathrm{C_{22}H_{24}O_{15}N_8}$. Calculated, %: C 41.25; H 3.75
Diiodomethylate: m.p. 234–235° (from aqueous alcohol), colorless needles.
Found, %: C 31.24; H 5.40
$\mathrm{C_{12}H_{24}ON_2J_2}$. Calculated, %: C 30.90; H 5.15
3,4-Bis(diethylaminomethyl)furan (IIIb). From 2 g of dichloride II, 15 ml of freshly distilled diethylamine, and 1 g of potassium hydroxide, as described above, 1.5 g (54%) of IIIb was obtained: a colorless liquid; b.p. 114–115° (5 mm); $n_D^{20}$ 1.4730; $d_4^{20}$ 0.9201; $MR_D$ 72.86, $\mathrm{C_{14}H_{26}ON_2F_2}$. Calculated: $MR_D$ 73.24.
Found, %: C 70.53, 70.80; H 11.03, 11.18
$\mathrm{C_{14}H_{26}ON_2}$. Calculated, %: C 70.54; H 10.99
Dipicrate: m.p. 160–161° (from aqueous alcohol), light-yellow crystals.
Found, %: C 44.79, 45.00; H 4.77, 4.81; N 15.79, 15.69
$\mathrm{C_{26}H_{32}O_{15}N_8}$. Calculated, %: C 44.83; H 4.63; N 16.09
Diiodomethylate: m.p. 175–176° (with decomposition, from absolute alcohol).
Found, %: C 36.73, 36.51; H 6.33, 6.29
$\mathrm{C_{16}H_{32}ON_2J_2}$. Calculated, %: C 36.79; H 6.18
3,4-Bis(N-pyrrolidinomethyl)furan (IIIb). From 3 g of II and 4.5 g of pyrrolidine in 25 ml of benzene with 2 g of caustic potash, as described above, 3.9 g (89%) of IIIb was obtained: a colorless liquid fuming in air; b.p. 141–142° (5 mm); $n_D^{20}$ 1.5070; $d_4^{20}$ 1.0204; $MR_D$ 68.49, $C_{14}H_{22}ON_2F_2$, calculated: $MR_D$ 68.84.
\[ \begin{aligned} &\text{Found \%: } C\ 72.09,\ 72.10;\ H\ 9.62,\ 9.79\\ &C_{14}H_{22}ON_2.\ \text{Calculated \%: } C\ 71.79;\ H\ 9.40 \end{aligned} \]
Dipicrate: m.p. 183–184° (from alcohol).
\[ \begin{aligned} &\text{Found \%: } C\ 45.26,\ 45.30;\ H\ 4.22,\ 4.26;\ N\ 16.05,\ 15.93\\ &C_{26}H_{28}O_{15}N_8.\ \text{Calculated \%: } C\ 45.09;\ H\ 4.07;\ N\ 16.18 \end{aligned} \]
Diiodomethylate: m.p. 197–198° (with decomp., from alcohol).
\[ \begin{aligned} &\text{Found \%: } C\ 37.23;\ H\ 5.51\\ &C_{16}H_{28}ON_2J_2.\ \text{Calculated \%: } C\ 37.06;\ H\ 5.40 \end{aligned} \]
3,4-Bis-(N-piperidinomethyl)furan (IIIc). From 1.3 g of II and 3.5 g of piperidine in 20 ml of abs. benzene with 1 g of caustic potash, as described above, 1.8 g (86%) of IIIc was obtained, distilling as a colorless liquid with b.p. 161–162° (5 mm), immediately crystallizing into colorless crystals; m.p. 26–27°.
\[ \begin{aligned} &\text{Found \%: } C\ 73.30,\ 73.40;\ H\ 10.03,\ 9.81\\ &C_{16}H_{26}ON_2.\ \text{Calculated \%: } C\ 73.24;\ H\ 9.99 \end{aligned} \]
Dipicrate: m.p. 183–184° (from aqueous alcohol).
\[ \begin{aligned} &\text{Found \%: } C\ 46.68,\ 46.85;\ H\ 4.54,\ 4.70\\ &C_{28}H_{32}O_{15}N_8.\ \text{Calculated \%: } C\ 46.67;\ H\ 4.48 \end{aligned} \]
Diiodomethylate: m.p. 223–224° (with decomp., from absolute alcohol), colorless needles.
\[ \begin{aligned} &\text{Found \%: } C\ 39.83,\ 39.84;\ H\ 6.08,\ 5.90\\ &C_{18}H_{32}ON_2J_2.\ \text{Calculated \%: } C\ 39.95;\ H\ 5.91 \end{aligned} \]
3,4-Bis-(N-morpholinomethyl)furan (IIId). From 1.8 g of II and 5 g of morpholine with 2 g of caustic potash in benzene, as described above, 2.7 g (92%) of IIId was obtained: a colorless liquid crystallizing on cooling; b.p. 156–158° (3 mm); m.p. 40–41°.
\[ \begin{aligned} &\text{Found \%: } C\ 62.94,\ 62.73;\ H\ 8.10,\ 8.36\\ &C_{14}H_{22}O_3N_2.\ \text{Calculated \%: } C\ 63.13;\ H\ 8.32 \end{aligned} \]
Dipicrate: m.p. 228–229° (with decomp., from aqueous alcohol).
\[ \begin{aligned} &\text{Found \%: } C\ 42.80;\ H\ 4.28\\ &C_{26}H_{28}O_{17}N_8.\ \text{Calculated \%: } C\ 43.10;\ H\ 3.88 \end{aligned} \]
Diiodomethylate: m.p. 226–227° (from absolute alcohol).
\[ \begin{aligned} &\text{Found \%: } C\ 35.07,\ 35.02;\ H\ 5.27,\ 5.19\\ &C_{16}H_{28}O_3N_2J_2.\ \text{Calculated \%: } C\ 35.56;\ H\ 5.19 \end{aligned} \]
Furan-3,4-dicarboxylic acid dichloride. To a suspension of 4.9 g of furan-3,4-dicarboxylic acid (m.p. 210–211°) (10) in 70 ml of abs. benzene, 20 ml of thionyl chloride was added portionwise, and the mixture was boiled for 15 h. After removal of the solvent, 6.1 g (98%) was obtained; m.p. 71–72° (from petroleum ether); colorless shiny plates.
\[ \begin{aligned} &\text{Found \%: } C\ 37.53,\ 37.49;\ H\ 1.10,\ 1.15\\ &C_6H_2O_3Cl_2.\ \text{Calculated \%: } C\ 37.31;\ H\ 1.03 \end{aligned} \]
3,4-Bis(N-pyrrolidinomethyl)furan (IIIb). To 15 ml of pyrrolidine in 50 ml of abs. ether, with cooling by ice water, by ...
4.8 g of dichloroanhydride in 50 ml of ether was added dropwise. The mixture was boiled for 2 h and left overnight. The precipitate of pyrrolidine hydrochloride was separated, and the ethereal solution of N,N′-bispyrrolidylamide of furan-3,4-dicarboxylic acid was added dropwise to a solution of 7 g of lithium aluminum hydride in 180 ml of absolute ether. The mixture was boiled for 5 h and decomposed with 200 ml of a 20% solution of Rochelle salt. The ethereal solution was dried with caustic potash. After removal of the solvent and distillation of the residue in vacuo, 1.7 g (40%) of IIIc was obtained: b.p. 129–131° (2 mm); $n_D^{20}$ 1.5095. A mixed sample of the dipicrate with the dipicrate described above showed no depression of the melting point.
Moscow State University
named after M. V. Lomonosov
Received
23 VI 1962
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